Field of the Invention
The present invention is in the field of cancer biology and pharmacotherapy of cancer diseases and conditions. More specifically, the present invention is giant obscurins and uses thereof.
Description of the Related Art
Obscurins comprise a family of giant, multidomain, cytoskeletal proteins originally identified in striated muscles where they play key roles in their structural organization and contractile activity (29, 31, 34). The human OBSCN gene spans 150 kb on chromosome 1q42 and undergoes extensive splicing to give rise to at least 4 isoforms (19, 38). The prototypical form of obscurin, obscurin A, is ˜720 kDa and contains multiple signaling and adhesion domains arranged in tandem (31). The NH2-terminus of the molecule contains repetitive immunoglobulin (Ig) and fibronectin-III (Fn-III) domains, while the COOH-terminus includes several signaling domains, including an IQ motif, a src homology 3 (SH3) domain, a Rho-guanine nucleotide exchange factor (Rho-GEF), and a pleckstrin homology (PH) domain, interspersed by non-modular sequences. In addition to obscurin A, the OBSCN gene gives rise to another large isoform, obscurin B or giant (g) MLCK, which has a molecular mass of ˜870 kDa (19, 38). Obscurin B contains two serine/threonine kinase domains, which replace the non-modular COOH-terminus of obscurin A (25). The two serine/threonine kinases may also be expressed independently as smaller isoforms, containing one (˜55 kDa) or both (˜145 kDa) kinase domains (6).
Early sequencing analysis of 13,023 genes in breast and colorectal cancers identified 189 candidate genes that were highly mutated (41). Of the 189 candidate genes, TP53 and OBSCN were the only commonly mutated genes in both tumor types (41). Additional analysis of OBSCN revealed a germline mutation in glioblastoma and novel somatic mutations in melanoma tumors (3). Moreover, whole genome array analysis of gastrointestinal stromal and leiomyosarcoma tumors indicated that the differential expression of OBSCN and PRUNE2 is a reliable two-gene expression classifier that can distinguish the two tumor types (36).
Obscurins are abundantly expressed in normal breast epithelial cells, where they localize at cell-cell junctions, the nucleus, and in cytoplasmic puncta coinciding with the Golgi membrane, but their expression is markedly diminished in breast cancer cells (33). Down-regulation of giant obscurins in non-tumorigenic MCF10A breast epithelial cells via shRNA technology conferred them with a survival advantage following exposure to DNA stress, due to reduced apoptosis, indicating that obscurins may play key roles in breast tumor suppression. Moreover, obscurin-depleted MCF10A cells acquired a mesenchymal appearance and exhibited increased cell scattering compared to control cells, which formed epithelial clusters.
The prior art is deficient in compositions and methods for prognosis and treatment of cancer. The present invention fulfills this longstanding need and desire in the art.